Use of Sodium–Glucose Cotransporter 2 Inhibitors in Hospitalized Patients

Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have noted benefits in the treatment of type 2 diabetes, cardiovascular disease, heart failure, and chronic kidney disease. Despite these benefits, the adoption of SGLT2i in clinical practice has been slow. Early initiation of SGLT2i during hospitalization has been proposed to address this gap for 2 important reasons: 1) it provides early clinical benefit in multiple disease states; and 2) hospitalization presents an opportunity for medication optimization and patient education, thereby overcoming clinical inertia. Challenges in SGLT2i adoption necessitate innovative strategies for integration into clinical practice. Ongoing trials and novel care delivery models are anticipated to further elucidate effective strategies for SGLT2i implementation and adherence. This review synthesizes the accrued evidence of SGLT2i across various chronic diseases. It emphasizes the rationale for early in-hospital initiation and discusses barriers and potential solutions for widespread implementation of SGLT2i in hospitalized patients.

discuss potential barriers and solutions for widespread in-hospital implementation of SGLT2i.

SGLT2i IN THE TREATMENT AND PREVENTION OF CHRONIC DISEASES
SGLT2i have demonstrated improved outcomes for patients with HF across the spectrum of LVEF in a number of pivotal clinical trials.5][6][7][8][9] Similar to those with HFrEF, pivotal trials for patients with HF with preserved ejection fraction (HFpEF) 1][12][13][14] These studies provided the first evidence of benefit from the addition of HF therapy for patients with improved ejection fraction, adding to evidence surrounding initiation and continuation of guideline-directed medical therapy (GDMT). 15veral major trials established the efficacy of SGLT2i in patients with T2DM and established CV disease.These included the CANVAS Program, 16 DECLARE-TIMI 58 trial, 17 EMPA-REG OUTCOME, 18 SCORED trial 19 which not only established the CVD benefit of SGLT2i in patients with T2D but also laid the groundwork for further studies to illustrate their benefits in patients with HF and CKD.These trials not only established the CVD benefit of SGLT2i in patients with T2D but also laid the groundwork for further studies to illustrate their benefits in patients with HF and CKD.
Finally, 3 major trials evaluated the efficacy of SGLT2i in patients with CKD with and without T2DM including the CREDENCE trial 20 , DAPA-CKD trial 21 , and the EMPA-Kidney trial. 22These trials demonstrated in patients with both reduced estimated glomerular filtration rate (eGFR) and albuminuria with SGLT2i, leading to reductions in kidney disease progression and kidney and CV-associated death.
The aforementioned pivotal trials and their key components are listed in Table 1.On the basis of these trials, the US Food and Drug Administration approved

INITIATION OF SGLT2i IN HOSPITALIZED PATIENTS
The initiation of SGLT2i in hospitalized patients has been a point of discussion on the basis of 2 important arguments: 1) potential benefits of early initiation of SGLT2i; and 2) hospitalizations providing an additional touch point for medication optimization and monitorization of potential adverse events (Central Illustration).
BENEFIT OF EARLY INITIATION OF SGLT2i.The SOLOIST-WHF and EMPULSE trials have underscored the advantages of commencing SGLT2i treatment early.In the SOLOIST-WHF study which included patients hospitalized due to worsening HF, the administration of sotagliflozin, which is a both SGLT2 and 1 inhibitor, either immediately prior to or shortly following discharge, resulted in a significant decrease in death from CV causes and hospitalizations and urgent visits for HF (HR 0.67; 95% CI 0.52-0.85;P < 0.001). 6milarly, the EMPULSE trial included patients hospitalized with a diagnosis of acute de novo or decompensated chronic HF and initiated empagliflozin when the patients were clinically stable in the hospital.The primary outcome was clinical benefit that was assessed using a win ratio and was defined as a hierarchical composite of death from any cause, number of HF events and time to first HF event, or a 5 point or greater change in KCCQ Total Symptoms Score at 90 days.Patients in the empagliflozin group had a higher rate of clinical benefit than the placebo HIGHLIGHTS SGLT2 inhibitors are effective in managing type 2 diabetes, cardiovascular diseases, heart failure, and chronic kidney disease.
Initiating SGLT2 inhibitors early during a hospital stay offers a strategic approach to optimize patient care and overcome barriers to initiation.
Advancements in care delivery methods will focus on addressing barriers to adoption and integrating innovative care models for wider implementation.Continued on the next page adverse events is one of the major reasons for physician and patient clinical inertia. 24Hospitalizations are additional touch points in the care of some patients with HF and they offer a unique opportunity  HFrEF was found to be relatively small and was associated with better clinical outcomes compared to a similar decline on placebo. 26

POTENTIAL BARRIERS AND SOLUTIONS FOR INITIATION OF SGLT2i IN HOSPITALIZED PATIENTS
Clinical inertia or deferral to outpatient care can pose significant barriers to the initiation of SGLT2i in hospitalized patients.This is often due to perceived lower clinical risk or reluctance to initiate a new therapy, especially among patients who appear clinically stable with relatively mild symptoms. 24However, as discussed above, data from DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, and DELIVER trials underscored the rapid clinical benefits observed with the SGLT2i, highlighting key opportunities for the early identification and prompt management of this patient population.8][29] When the GDMT is started before hospital discharge, the compliance with GDMT posthospitalization and the chance of target-dose achievement in the short-and longerterm follow-up increases significantly. 29In the IMPACT-HF trial, at 60 days follow-up, patients started on carvedilol predischarge had higher use of beta-blockers than those who did not (91.2%vs 73.4%, P < 0.0001).Multiple strategies have been investigated to increase the initiation of GDMT during hospitalization.One potential strategy is to create teams to rapidly identify hospitalized patients with HF who are not on optimal medical therapy and intervene to recommend GDMT optimization.
IMPLEMENT-HF investigated if this strategy can be implemented by using a virtual multidisciplinary team of physicians and pharmacists and showed that the virtual care team-based strategy improved the net intensification of GDMTduring a hospitalization (44% vs 24% for net intensification, P ¼ 0.002). 30Similarly, in a pilot-randomized trial that investigated the efficacy of a virtual HF intervention on GDMT optimization on patients with HFrEF admitted with any cause showed a mean improvement of 0.75 in optimal medical therapy score at discharge in the intervention group compared.GDMT and support for managing symptoms, thus potentially reducing rehospitalization rates and improving survival outcomes for patients with HF. 8 In a meta-analysis that pooled the randomized clinical trials investigating the effectiveness of pharmacist-involved multidisciplinary teams for the management of HF, it found a notable decrease in the rates of hospitalizations due to HF (OR: 0.72, 95%CI 0.55-0.93,P ¼ 0.01, I2 ¼ 39%) and in hospitalizations for any cause (OR: 0.76, 95% CI: 0.60-0.96,P ¼ 0.02, I2 ¼ 52%), which can be attributed, in part, to improved adherence to medication regimens.Additionally, they observed significant enhancements in the understanding of HF among participants. 31ovider knowledge and comfort with the medication class are crucial for the successful initiation of SGLT2i in hospitalized patients.Therefore, recurring and iterative education of providers regarding benefits and potential adverse effects of SGLT2i is important.In PROMPT-HF trial, providers were given access to a customized order set that displayed all available medications within the classes not currently prescribed, listed alphabetically along with their indication. 32This was supplemented with a hyperlink to the study webpage that contained informational documents expanding on evidence-based medical therapy recommended by current guidelines for patients with HFrEF.This approach was found to be effective in increasing provider knowledge and comfort level with HFrEF guidelines.In addition to the potential expected effects, providers should also be educated about adjustments in diabetic and diuretic regimens when initiating SGLT2is.Notably, in the pivotal trials, hypoglycemic events were rare and occurred at similar rates in those without diabetes. 4,5netheless, combining SGLT2is with insulin or agents that stimulate insulin production (like glinides and sulfonylureas) could elevate hypoglycemia risk; therefore, it has been recommended to lower the dosage of sulfonylureas or glinides by half or reduce basal insulin by 20% upon initiating SGLT2i treatment, particularly if the patient's HbA1C is within the normal range or if they have a history of hypoglycemia. 33,34Similarly, studies investigated diuretic effects of SGLT2i, and its interplay with loop diuretics showed that it was effective across all spectrums of loop diuretic doses, and the diuretic dose did not change in most patients during follow-up and the

Inpatient SGLT2i Initiation
J U L Y 2 0 2 4 : 1 0 1 0 2 4 change were similar to the placebo group. 35Therefore, provider education on the generally minimal to no adjustments required for diuretics could help reduce concerns related to monitoring and following up with patients.
A particular focus should be given to education about the expected effects of SGTL2i on eGFR.Concerns for a decline in eGFR are common when initiating SGLT2i therapy and can be a barrier for initiation or inappropriate discontinuation of SGLT2i.
Importantly, a secondary analysis of the DAPA-HF trial showed that the mean reduction in eGFR after dapagliflozin was 4.2 ml/min/1.73m 2 compared to 1.1 ml/min/1.73m 2 in the placebo group.However, this initial decline was not associated with higher rates of long-term worsening kidney function or other adverse events.In fact, those with more than 10% eGFR decline in the dapagliflozin group had a lower rate of primary outcome which was a composite of worsening HF or CV death, 26 suggesting this is likely to be a pharmcodynamic effect of the therapy rather than true acute kidney injury.
The safety data from existing clinical trials for SGLT2i showed that the number of safety events were low and consistent across trials.In the SOLOIST-WHF trial, sotagliflozin was administered to patients with diabetes who had recently been hospitalized for worsening HF.Diarrhea was more common with sotagliflozin than with placebo (6.1% vs 3.4%), as was severe hypoglycemia (1.5% vs 0.3%). 6However, the percentage of patients with hypotension was similar in the sotagliflozin group and the placebo group (6.0% and 4.6%, respectively), as was the percentage with acute kidney injury (4.1% and 4.4%, respectively).In the EMPULSE trial, empagliflozin was initiated in patients hospitalized for acute HF, regardless of LVEF.There were no significant differences of safety events between the empagliflozin group and the placebo group for volume depletion (12.7% vs 10.2%, respectively), hypoglycemia (1.9%, 1.5%, respectively), acute renal failure (7.7% vs 12.1%, respectively), and urinary tract infection (4.2% vs 6.4%, respectively). 23Overall, serious adverse events were reported in 32.3% of the empagliflozin-treated patients and 43.6% of the placebo-treated patients.
These findings suggest that SGLT2i can be safely initiated in hospitalized patients, providing significant clinical benefits in the months following treatment initiation.
The cost and lack of cost transparency of SGLT2i is another significant consideration in their use.While the specific cost of these medications can vary based on factors such as location, insurance coverage, and specific medication, they are generally more expensive than some other classes of GDMT given that they have been added to the armamentarium of HF therapies.However, they can provide significant health benefits in patients with multiple comorbidities including T2D, CAD, CKD, and HF.Therefore, the trade-offs between health benefits of SGLT2i and increased costs should be carefully examined to justify their clinical use.The cost-effectiveness of treatments for HF, including SGLT2is, is a complex issue with multiple perspectives.The value of treatment is often framed within a willingness-to-pay model, which can vary significantly among stakeholders such as patients, healthcare providers, and insurance companies.Cost per quality-adjusted life year (QALY) is a common measure of value, with <$50,000 per QALY is considered high value and $$150,000 per QALY is considered low value. 36wever, perspectives on what constitutes a costeffective intervention can differ.For example, the American College of Cardiology and American Heart Association consider a health intervention that exceeds 3 times the GDP per capita per QALY as not cost-effective. 37From the patient's perspective, the concept of value also includes out-of-pocket costs and insurance premiums.The cost differences between HF treatments can significantly impact a patient's willingness to pay for a treatment and affect patients' adherence to treatment regimens. 38Therefore, the cost of SGLT2is is a crucial factor in their adoption and use, and it represents a significant barrier that needs to be addressed to improve patient outcomes.Importantly, in a cost-effectiveness analysis based on a hypothetical cohort with patients similar to DAPA-HF trial cohort showed that dapagliflozin had an incremental cost-effectiveness ratio of $68,300 per QALY gained (95% UI: $54,600-$117, 600 per QALY gained) which makes it cost-effective at current US prices. 39However, recent analyses from Medicare data underscore the significant financial burden these medications can impose on patients.In 2020, Medicare plans often required tier 3 costsharing for SGLT2i, with median annual out-ofpocket (OOP) costs for quadruple therapy, including SGLT2i, reaching $2,217. 40This is in stark contrast to a fully generic regimen, excluding SGLT2i/ARNIs, which had a median annual OOP cost of merely $3. 40 Such high OOP costs likely render SGLT2i therapies unaffordable for many Medicare beneficiaries, despite their proven efficacy and the guidelines recommending their use in HFrEF.Moreover, the restriction of coverage through high-tier cost-sharing and the complexities around insurance policies further complicate patient access to these life-saving medications, highlighting a critical need for policy Unlu et al Inpatient SGLT2i Initiation reforms aimed at reducing medication costs and improving transparency in drug pricing. 41Only through concerted efforts to address these cost barriers can we ensure broader patient access to SGLT2i, thereby leveraging their full potential in improving outcomes for patients with HF and other comorbid conditions.
Finally, patients with indications to use SGLT2i often have multiple comorbidities requiring several medications, which can lead to complex medication regimens.This complexity can lead to medication nonadherence, adverse drug reactions, and decreased quality of life which in turn can play a role in patients' decisions to use SGLT2i.As an example, 1 observational study found that 84% of patients with HF used 5 or more medications at hospital admission and 42% used 10 or more medications. 42In addition, patients who have non-GDMT polypharmacy were less likely to achieve optimization of GDMT on follow-up. 43erefore, careful review of patients' medications should be performed for each patient and non-GDMT medications that pose harm or minimal benefit should be deprescribed.Hospitalizations provide a great opportunity to achieve this and monitor for potential adverse events following multiple medication changes.Furthermore, SGLT2i has been shown to reduce the risk of hyperkalemia, potentially enabling the use of renin aldosterone angiotensin inhibitors and mineralocorticoid receptor antagonists. 44 are on the verge of digital transformation in  3).
In addition to possibly expanding the role of SGLT2i with the results of these trials, implementation research will be fundamental in accelerating the uptake and utilization of proven therapies and establishing innovative care delivery models such as PROMPT-HF and IMPLEMENT-HF.It is highly important to examine not only the efficacy of new care delivery models but also their impacts on costs and burden on patients and providers.Another approach to rapid initiation of SGLT2i has been to initiate and titrate the medications either right before or shortly after the hospitalization.STRONG-HF investigated such a strategy with initiation of 4 class GDMT at hospital discharge for patients with HFrEF followed by rapid up-titration posthospitalization. 45 The study showed that the intensive strategy reduced the composite of HF readmission or all-cause death up to day 180 and did not increase serious adverse events.However, real-world implementation and scaling of such a program requires substantial resources and is difficult to sustain when the costs associated with HF management are already excessive.As a potential mitigation strategy, remote care strategies can be effective.A remote team-based strategy in a nonrandomized study using algorithms was shown to be a successful strategy for rapid GDMT initiation in patient with HFrEF. 46To further investigate this strategy in a larger patient population with all HF, the COPILOT-HF trial (NCT05734690) was designed.COPILOT-HF is a pragmatic randomized trial to determine if a remote clinic that implements a standardized, stepped-approach to medication optimization in patients with HF will achieve a higher rate of GDMT than a strategy of patient and provider education followed by remote HF clinic management.Inpatient SGLT2i Initiation models are expected to provide further insights into the optimal use of SGLT2i in various clinical settings and appropriate integration into practice.

CONCLUSIONS
the following: 1) in 2016, empagliflozin to reduce the risk of CV death in adults with T2D and established CV disease; 2) in September 2019, canagliflozin to treat diabetic kidney disease; 3) in May 2020, dapagliflozin for HFrEF; 4) in May 2021, dapagliflozin to treat patients with CKD at risk of disease progression, regardless of diabetes and albuminuria status; and 5) in September 2022, empagliflozin for HFpEF, and September 2023, empagliflozin for CKD without DM or HF.
LVEF = left ventricular ejection fraction OOP = ou-of-pocket QALY = quality-adjusted life year SGLT2i = sodium-glucose cotransporter 2 inhibitor T2D = type 2 diabetes group (stratified win ratio: 1.36; 95% CI: 1.09-1.68;P ¼ 0.0054) regardless of the ejection fraction, acute vs chronic HF, or the presence of diabetes. 23In addition, secondary analyses of DAPA-HF, EM-PEROR-Reduced, EMPEROR-Preserved, and DELIVER were conducted to investigate time to clinical benefit of SGLT2i in HF across the LVEF spectrum.DAPA-HF showed that the composite of CV death or worsening HF was lower with dapagliflozin.The statistical significance of this benefit was sustained by 28 days after randomization (HR at 28 days: 0.51 [95% CI: 0.28-0.94];P ¼ 0.03).The upper confidence boundary of the HR remained below unity for the remainder of the trial.A similar pattern of early and consistent benefit was observed for the individual components of the primary efficacy outcome (worsening HF: HR at . These effects were seen early and consistently.Statistical significance for separation between the empagliflozin and the placebo arms occurred by day 18 for time to CV death or HF hospitalization (HR at 18 days 0.41, 95% CI: 0.17-0.99),after which this benefit was sustained with the boundary of the upper CI below unity for the rest of the trial period.Finally, The DELIVER trial showed that dapagliflozin reduced CV death or worsening HF events in patients with HF with mildly reduced or preserved ejection fraction.The time to first nominal statistical significance for the primary endpoint was 13 days (HR: 0.45; 95% CI: 0.20-0.99;P ¼ 0.046), and significance was sustained from day 15 onwards.First and sustained statistical significance was reached for worsening HF events (HR: 0.45; 95% CI: 0.21-0.96;P ¼ 0.04) by day 16 after randomization.Significant benefits for the primary endpoint and worsening HF events were sustained at 30 days, 90 days, 6 months, 1 year, 2 years, and final follow-up (primary endpoint: HR: 0.82; 95% CI: 0.73-0.92;worsening HF events: HR: 0.79; 95% CI: 0.69-0.91).USING HOSPITALIZATION AS AN OPPORTUNITY FOR MEDICATION OPTIMIZATION.Clinical inertia is one of the most important barriers for initiation of GDMT in HF with many potential contributing physician, patient, and system factors.The fear of medication to overcome inertia by allowing close monitoring of adverse events after initiation or up-titration of medications.In addition, it also gives the clinical team a chance to educate the patient about their disease and potential treatments, as well as address potential issues around cost before discharge.During hospitalization, there is a unique opportunity to educate patients about HF, its management, and the importance of adhering to the medication regimen.Studies have shown that effective communication about reasons for medication prescriptions and potential adverse drug events is critical and can improve adherence to therapies.Therefore, hospitalizations can provide the time for various members of the clinical team to educate the patients and reinforce the importance of HF therapies. 25In addition, hospitalizations provide an opportunity for a monitored setting to observe tolerability of prescribed HF therapies where any adverse events can be promptly addressed.It might also prevent reactionary and incorrect discontinuation of therapies based on findings such as an expected transient change in renal function, described as eGFR dip.The initial decline in eGFR after initiation of dapagliflozin in patients with CENTRAL ILLUSTRATION Challenges and Opportunities for Inpatient SGLT2i Initiation Unlu O, et al.JACC Adv.2024;3(7):101024.J A C C : A D V A N C E S , V O L . 3 , N O .7 , 2 0 2 4 An emerging concern among clinicians is the discharge of patients on SGLT2i, without ensuring adequate follow-up.This apprehension stems from potential challenges patients may face in adhering to their treatment plan, recognizing and managing side effects, and accessing necessary healthcare services postdischarge.Effective communication and establishing a clear, accessible follow-up plan are paramount to address these concerns.Therefore, the most recent AHA/ACC/HFSA guidelines for the management of HF highlight the importance of comprehensive care management, including the use of multidisciplinary teams.These teams can facilitate healthcare and innovative health delivery strategies that takes advantage of rapidly emerging technologies, which has the potential to address economic challenges in the treatment of HF.Remote patient encounters, telehealth, and mobile health are some of the platforms paving the way for an expansion of virtual care.These platforms are being used to gather health data, share it with healthcare providers, and empower patients for self-management of chronic diseases which can increase quality, reduce costs, and improve the coordination of care.38 ONGOING TRIALS AND FUTURE DIRECTIONSSeveral trials are currently underway to further investigate the benefits of SGLT2i in various patient populations and settings including EMPACT-MI, DICTATE-AHF, DAPA-ACT HF TIMI 68, and the ertugliflozin in AHF trial (Table 2).Furthermore, several implementation studies are being conducted to investigate a variety of interventions to improve SGLT2i prescriptions or broader GDMT initiation (Table SGLT2i have shown significant promise in the treatment and prevention of chronic diseases such as HF, T2D, CAD, and CKD.The results of various clinical trials have demonstrated the efficacy and safety of SGLT2i in these patient populations.Despite the evidence, utilization of SGLT2i remains low and hospitalizations provide a potential opportunity to improve prescription rates.To overcome the potential barriers to initiation of SGLT2i in hospitalized patients, such as clinical inertia, provider knowledge, cost, and patient preference, innovative strategies need to be developed.Ongoing trials to expand the indications of SGLT2i as well as novel care delivery

TABLE 1
Pivotal Trials for Sodium-Glucose Cotransporter 2 Inhibitor